Study of Tazemetostat in Newly Diagnosed Diffuse Large B Cell and Follicular Lymphoma Patients Treated by Chemiotherapy

NCT ID: NCT02889523

Last Updated: 2024-10-09

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 214 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2026-04-30

Brief Summary

Phase I of the study is designed to determine the recommended phase II dose (RP2D) for tazemetostat in patients treated with 8 cycles of R-CHOP 21.

Phase II of the study is designed to determine the safety and the efficacy of tazemetostat in DLBCL and FL patients :

DLBCL : tazemetostat with 6 cycles of R-CHOP 21 + 2 cycles of Rituximab FL : tazemetostat with 6 cycles of R-CHOP 21 + 2 cycles of Rituximab then maintenance with 6 months of tazemetostat and 24 months of Rituximab

Detailed Description

Phase I:

Up to 18 patients will be recruited, using a conventional dose-escalation algorithm (3+3 patients per dose level) to identify the maximum tolerated dose (MTD) which will be deemed the RP2D. Patients will receive 8 cycles of RCHOP every 21 days and tazemetostat every day, starting on day 2 of cycle 1.

4 cohorts are defined, according to dose levels of tazemetostat: 400mg Twice a day (BID) (cohort 1, starting level), 600mg BID (cohort 2), 800mg BID (cohort 3), 200mg BID (cohort -1), depending on the observed toxicities.

Phase II:

Up to 184 patients (122 DLBCL and 62 FL) will be recruited and treated with tazemetostat at the MTD and RCHOP.

Patients will receive 6 cycles of RCHOP every 21 days and tazemetostat at the MTD every day, starting on day 2 of cyle 1, + 2 cycles of Rituximab+tazemetostat. For FL, a maintenance of tazemetostat (6 months) + rituximab (24 months) is expected

Conditions

Lymphoma; DLBCL; Follicular Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DLBCL cohort

RCHOP + tazemetostat:

• RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1): Phase I : 8 cycles, every 21 days Phase II : 6 cycles, every 21 days

• Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days
• Tazemetostat: PO, doses according to dose cohorts for phase I, and at RP2D for phase II: continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Tablets 200 mg, to be administrated per os

Rituximab

Intervention Type: DRUG

375 mg/m²/dose, D1

Cyclophosphamide

Intervention Type: DRUG

750 mg/m²/dose, D1

Vincristine

Intervention Type: DRUG

1.4 mg/m²/dose (max 2 mg), D1

Doxorubicin

Intervention Type: DRUG

50 mg/m²/dose, D1

Prednisolone

Intervention Type: DRUG

40 mg/m2 in the morning D1 to D5

FL cohort

RCHOP + tazemetostat:

Induction

• RCHOP: rituximab (IV, 375 mg/m², day 1), Prednisolone (PO, 40 mg/m² in the morning, day 1 to day 5), doxorubicine (IV, 50 mg/m², day 1), cyclophosphamide (IV, 750 mg/m², day 1), vincristine (IV, 1.4 mg/m², day 1):

6 cycles, every 21 days

• Rituximab (IV, 375 mg/m², day 1) Phase II : 2 cycles, every 21 days
• Tazemetostat: PO, RP2D, continuous: Cycle 1: 2 to 21 BID, Cycle 2-8: 1 to 21 BID

Maintenance

• Tazemetostat : 6 months (every 8 weeks)
• Rituximab : 24 months (every 8 weeks)

Group Type: EXPERIMENTAL

Tazemetostat

Intervention Type: DRUG

Tablets 200 mg, to be administrated per os

Rituximab

Intervention Type: DRUG

375 mg/m²/dose, D1

Cyclophosphamide

Intervention Type: DRUG

750 mg/m²/dose, D1

Vincristine

Intervention Type: DRUG

1.4 mg/m²/dose (max 2 mg), D1

Doxorubicin

Intervention Type: DRUG

50 mg/m²/dose, D1

Prednisolone

Intervention Type: DRUG

40 mg/m2 in the morning D1 to D5

Interventions

Tazemetostat

Tablets 200 mg, to be administrated per os

Intervention Type: DRUG

Rituximab

375 mg/m²/dose, D1

Intervention Type: DRUG

Cyclophosphamide

750 mg/m²/dose, D1

Intervention Type: DRUG

Vincristine

1.4 mg/m²/dose (max 2 mg), D1

Intervention Type: DRUG

Doxorubicin

50 mg/m²/dose, D1

Intervention Type: DRUG

Prednisolone

40 mg/m2 in the morning D1 to D5

Intervention Type: DRUG

Other Intervention Names

EPZ-6438; Mabthera

Eligibility Criteria

Inclusion Criteria

• for Cohort DLBCL ONLY

• 1-Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) with

• Phase Ib aaIPI ≥ 2
• Phase II: aaIPI ≥ 1ONLY
• 2. Age between 60 and 80 years included
• for Cohort FOLLICULAR ONLY

• 1-High Tumor Burden (as defined by GELF criteria > 0) frontline follicular lymphoma (FL) with high risk FLIPI 3-5
• 2. Aged between 18 years and 80 years included
• 11bis. Females of childbearing potential (FCBP) must agree to use one reliable form of contraception or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 12 months after discontinuation of any study treatments (R-CHOP, tazemetostat, Rituximab)
• For both Cohorts

• 1bis- For phase II patients: Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan and/or clinical examination AND a FDG avid disease by PETscan
• 3.ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
• 4.Signed informed consent
• 5.Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
• 6.Adequate renal function as calculated by a creatinine clearance > 40 mL/min by local institutional formula
• 7. Adequate bone marrow function as defined as:

• ANC ≥ 1500/mm3 (≥ 1.5 X 109/L)
• Platelets ≥ 75,000/mm3 (≥ 75 X 109/L) without platelet transfusion dependency during the last 7 days
• Hemoglobin ≥ 9 g/dL (may receive transfusion)
• 8. Adequate liver function as defined as:

• Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
• Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN (or ≤ 5 X ULN if related to lymphoma involvement)
• Patients with prior Hepatitis B and C are eligible if, for Hepatitis B detection, surface antigen is negative and/or HBV DNA is undetectable, and for Hepatitis C detection, if HCV RNA is undetectable.
• 9. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
• 10. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11
• 11. Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
• 12. Patient covered by any social security system (for France only)
• 13. Patient who understands and speaks one of the country official languages

Exclusion Criteria

• for Cohort DLBCL

___15-Previous treatment for B cell lymphoma, except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)

• for Cohort FOLLICULAR ONLY

• 14bis. Prior therapy for lymphoma including radiotherapy except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)
• 17-Pregnant or lactating females
• For both Cohorts

• 1-Central nervous system or meningeal involvement
• 2-Contraindication to any drug contained in the chemotherapy regimen
• 3-Prior treatment with tazemetostat or other inhibitor of EZH2
• 4-Patients who are undergoing active treatment for another malignancy, exceptions include: A patient who has been disease free for 2 years, or a patient with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible Patients with prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia(AML) or prior history of T-LBL/T-ALL are excluded whatever receiving treatment or not and whatever date of diagnosis of these pathologies
• 5-Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
• 6-Patients unwilling to exclude St. John's wort, Seville oranges, grapefruit juice and/or grapefruit from diet
• 7-Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted within 2 weeks of enrollment)
• 8-Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat
• 9-Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of tazemetostat or ventricular arrhythmia
• 10-Not applicable
• 11-Active uncontrolled infection requiring systemic therapy
• 12-Congenital immunodeficiency or known HIV (human immunodeficiency virus infection)
• 13-Any other major illness, that in the investigator's judgement, will substantially increase the risk associated with the patient's participation in the study
• 14-Patients who have undergone a solid organ transplant
• 16-Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy
• 18-Person deprived of his/her liberty by a judicial or administrative decision
• 19-Adult person under legal protection
• 20-Person hospitalized without consent
• 21-Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Epizyme, Inc.

INDUSTRY

Sponsor Role: collaborator

The Lymphoma Academic Research Organisation

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vincent Ribrag, MD

Role: STUDY_CHAIR

Institut Gustave Roussy Cancer Campus Grand Paris

Clémentine Sarkozy, MD

Role: STUDY_CHAIR

Institut Gustave Roussy Cancer Campus Grand Paris

Franck Morshhauser, Pr

Role: STUDY_CHAIR

Centre Régional Hospitalier de Lille

Loic Ysebaert, MD

Role: STUDY_CHAIR

IUCT Oncopole de Toulouse

Locations

Institut Jules Bordet

Brussels, , Belgium

CHU de Liege

Liège, , Belgium

CHRU Mont Godinne

Yvoir, , Belgium

Centre Hospitalier Victor Dupouy

Argenteuil, , France

CH d'Avignon - Hôpital Henri Dufaut

Avignon, , France

CHU de Besançon - Hôpital Jean Minjoz

Besançon, , France

Polyclinique Bordeaux Nord Aquitaine

Bordeaux, , France

CH de Chambéry

Chambéry, , France

CHU d'Estaing

Clermont-Ferrand, , France

APHP - Hopital Henri Mondor

Créteil, , France

CHU de Dijon

Dijon, , France

CHU Grenoble

Grenoble, , France

CH Départemental de Vendée

La Roche-sur-Yon, , France

CHRU Lille - Hôpital Claude Huriez

Lille, , France

Chu de Limoges - Hopital Dupuytren

Limoges, , France

Centre Leon Berard

Lyon, , France

Institut Paoli Calmette

Marseille, , France

CHU de Montpellier - Hôpital Saint-Eloi

Montpellier, , France

CHU de Nantes - Hôtel Dieu

Nantes, , France

APHP - Hôpital de la Pitié Salpetrière

Paris, , France

APHP - Hôpital Saint Louis

Paris, , France

CH de Perpigan

Perpignan, , France

CHU Lyon Sud

Pierre-Bénite, , France

Chu de Poitiers - Hopital de Miletrie

Poitiers, , France

CHU de Rennes - Hôpital Pontchaillou

Rennes, , France

Centre Henri Becquerel

Rouen, , France

Centre Rene Hugenin

Saint-Cloud, , France

Institut de cancérologie de la Loire

Saint-Priest-en-Jarez, , France

CHRU de Strasbourg

Strasbourg, , France

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, , France

Institut Gustave Roussy

Villejuif, , France

Countries

Belgium; France

References

Sarkozy C, Morschhauser F, Dubois S, Molina T, Michot JM, Cullieres-Dartigues P, Suttle B, Karlin L, Le Gouill S, Picquenot JM, Dubois R, Tilly H, Herbaux C, Jardin F, Salles G, Ribrag V. A LYSA Phase Ib Study of Tazemetostat (EPZ-6438) plus R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) with Poor Prognosis Features. Clin Cancer Res. 2020 Jul 1;26(13):3145-3153. doi: 10.1158/1078-0432.CCR-19-3741. Epub 2020 Mar 2.

Reference Type: DERIVED

PMID: 32122924 (View on PubMed)

Other Identifiers

Epi-RCHOP

Identifier Type: -

Identifier Source: org_study_id